There is a well-documented association between cardiovascular disease morbidity and mortality and increased levels of ambient fine particulate air pollution (PM2.5). Stroke is a common manifestation of cardiovascular disease and a leading cause of death, hospitalization, and long-term disability in the United States. PM2.5 may also increase the risk of ischemic and/or hemorrhagic stroke, but few studies have specifically addressed this hypothesis and results remain equivocal. Other important gaps in this literature include: identification of especially susceptible individuals; evaluation of the effects of PM2.5 component species, gaseous pollutants (CO, NO2, SO2, and ozone) and specific air pollution sources; and delineation of the time scale of effects. We propose to evaluate in unprecedented detail the association between exposure to individual ambient pollutants and pollutant mixtures and the risk of stroke among 159,643 post-menopausal women participating in the Women's Health Initiative and 45,358 men participating in the Health Professionals Follow-Up Study. Specifically, using data from these two national, prospective cohorts we will: (1) evaluate the effects of long- term (i.e.: years) and short-term (i.e.: days) exposure to ambient pollutants on the risk of ischemic and hemorrhagic stroke, (2) assess whether participants with diabetes mellitus and other stroke risk factors are especially susceptible to these effects, (3) examine whether the strength of association varies by ischemic stroke subtypes, and (4) evaluate these associations within a novel multi-pollutant framework. To accomplish these aims we will estimate each participant's exposure to PM2.5, PM2.5 component species, gaseous pollutants, and pollutant mixtures using validated state-of-the-art geostatistical models, and relate each individual's exposure to the risk of ischemic and hemorrhagic stroke. This proposal offers several advantages over existing studies, including two well characterized study populations, detailed data on each stroke event, large sample size, geographic diversity, the ability to examine short-term and long-term effects jointly, novel statistical methods to reduce measurement error, and the opportunity to assess multiple pollutants simultaneously within a novel multi-pollutant framework. By better quantifying the relationship between ambient air pollutants and pollution mixtures and specific stroke types, and by identifying susceptible populations, the results of this project will contribute to regulatory policy with important implications for stroke prevention, and may help to inform the planning of future mechanistic studies. PUBLIC HEALTH RELEVANCE: Stroke is a leading cause of death, hospitalization, and disability in the United States. Studies suggest that exposure to outdoor air pollution may increase the risk of stroke, but this hypothesis has not been evaluated in detail. We propose to use novel methods and approaches to evaluate this hypothesis in detail within the context of two large, national studies including 161,000 post-menopausal women and 51,000 men. The results of this project will likely have important implications for stroke prevention through futur changes in public health policy.